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1.
Arthritis Res Ther ; 26(1): 139, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39054558

RESUMO

OBJECTIVES: Neutrophils and neutrophil extracellular traps (NETs) contribute to the vascular complications of multiple diseases, but their role in systemic sclerosis (SSc) is understudied. We sought to test the hypothesis that NETs are implicated in SSc vasculopathy and that treatment with prostacyclin analogs may ameliorate SSc vasculopathy not only through vasodilation but also by inhibiting NET release. METHODS: Blood from 125 patients with SSc (87 diffuse cutaneous SSc and 38 limited cutaneous SSc) was collected at a single academic medical center. Vascular complications such as digital ulcers, pulmonary artery hypertension, and scleroderma renal crisis were recorded. The association between circulating NETs and vascular complications was determined using in vitro and ex vivo assays. The impact of the synthetic prostacyclin analog epoprostenol on NET release was determined. RESULTS: Neutrophil activation and NET release were elevated in patients with SSc-associated vascular complications compared to matched patients without vascular complications. Neutrophil activation and NETs positively correlated with soluble E-selectin and VCAM-1, circulating markers of vascular injury. Treatment of patients with digital ischemia with a synthetic prostacyclin analog boosted neutrophil cyclic AMP, which was associated with the blunting of NET release and reduced NETs in circulation. CONCLUSION: Our study demonstrates an association between NETs and vascular complications in SSc. We also identified the potential for an additional therapeutic benefit of synthetic prostacyclin analogs, namely to reduce neutrophil hyperactivity and NET release in SSc patients.


Assuntos
Epoprostenol , Armadilhas Extracelulares , Escleroderma Sistêmico , Humanos , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Feminino , Masculino , Escleroderma Sistêmico/tratamento farmacológico , Pessoa de Meia-Idade , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Epoprostenol/farmacologia , Adulto , Idoso , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/imunologia , Ativação de Neutrófilo/efeitos dos fármacos , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia
2.
Respir Med ; 231: 107734, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38986791

RESUMO

BACKGROUND: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies. STUDY DESIGN AND METHODS: The multicenter, prospective, real-world, observational ADAPT Registry study followed adult patients with PAH for up to 78 weeks after initiating oral treprostinil (NCT03045029). Dosing, titration, and transitions of oral treprostinil were at the discretion of the prescriber. Patient-reported incidence and treatment of common side effects were collected to understand side effect management and tolerability. Insights from literature and expert recommendations were added to provide a consolidated resource for oral treprostinil use. RESULTS: In total, 139 participants in ADAPT completed ≥1 weekly survey; (median age 60.0 years, 76 % female). Median treatment duration of oral treprostinil was 13.1 months. During early therapy (Months 1-5), 62 % (78/126) of patients reported headache and diarrhea, and 40 % (50/126) reported nausea. At Month 6, many patients who reported side effects during early therapy reported an improvement (61 % headache, 44 % diarrhea, 70 % nausea). Common side effect treatments, including acetaminophen, loperamide, and ondansetron, were effective. Approximately one-quarter of patients reporting the most common side effects were untreated at Month 6. CONCLUSION: Patient selection for, and initiation and titration of, oral treprostinil should be individualized and may include parenteral treprostinil induction-transition for faster titration. Assertive side effect management may help patients reach higher and more efficacious doses of oral treprostinil.


Assuntos
Anti-Hipertensivos , Epoprostenol , Hipertensão Arterial Pulmonar , Humanos , Epoprostenol/análogos & derivados , Epoprostenol/administração & dosagem , Epoprostenol/efeitos adversos , Epoprostenol/uso terapêutico , Pessoa de Meia-Idade , Feminino , Masculino , Administração Oral , Estudos Prospectivos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Idoso , Consenso , Hipertensão Pulmonar/tratamento farmacológico , Adulto , Resultado do Tratamento , Cefaleia/induzido quimicamente , Sistema de Registros , Náusea/induzido quimicamente
3.
Cells ; 13(13)2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38994957

RESUMO

Platelet activation is critical for haemostasis, but if unregulated can lead to pathological thrombosis. Endogenous platelet inhibitory mechanisms are mediated by prostacyclin (PGI2)-stimulated cAMP signalling, which is regulated by phosphodiesterase 3A (PDE3A). However, spatiotemporal regulation of PDE3A activity in platelets is unknown. Here, we report that platelets possess multiple PDE3A isoforms with seemingly identical molecular weights (100 kDa). One isoform contained a unique N-terminal sequence that corresponded to PDE3A1 in nucleated cells but with negligible contribution to overall PDE3A activity. The predominant cytosolic PDE3A isoform did not possess the unique N-terminal sequence and accounted for >99% of basal PDE3A activity. PGI2 treatment induced a dose and time-dependent increase in PDE3A phosphorylation which was PKA-dependent and associated with an increase in phosphodiesterase enzymatic activity. The effects of PGI2 on PDE3A were modulated by A-kinase anchoring protein (AKAP) disruptor peptides, suggesting an AKAP-mediated PDE3A signalosome. We identified AKAP7, AKAP9, AKAP12, AKAP13, and moesin expressed in platelets but focussed on AKAP7 as a potential PDE3A binding partner. Using a combination of immunoprecipitation, proximity ligation techniques, and activity assays, we identified a novel PDE3A/PKA RII/AKAP7 signalosome in platelets that integrates propagation and termination of cAMP signalling through coupling of PKA and PDE3A.


Assuntos
Proteínas de Ancoragem à Quinase A , Plaquetas , Proteínas Quinases Dependentes de AMP Cíclico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3 , Epoprostenol , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Humanos , Proteínas de Ancoragem à Quinase A/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Epoprostenol/metabolismo , Epoprostenol/farmacologia , Fosforilação , AMP Cíclico/metabolismo , Transdução de Sinais
4.
Anesth Analg ; 139(2): 385-396, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39008867

RESUMO

BACKGROUND: Currently, clinical indicators for evaluating endothelial permeability in sepsis are unavailable. Endothelium-derived extracellular vesicles (EDEVs) are emerging as biomarkers of endothelial injury. Platelet endothelial cell adhesion molecule (PECAM) and vascular endothelial (VE)-cadherin are constitutively expressed endothelial intercellular adhesion molecules that regulate intercellular adhesion and permeability. Herein, we investigated the possible association between EDEVs expressing intercellular adhesion molecules (PECAM+ or VE-cadherin+ EDEVs) and endothelial permeability and sepsis severity. METHODS: Human umbilical vein endothelial cells (HUVECs) were stimulated with tumor necrosis factor alpha (TNF-α) directly or after pretreatment with permeability-modifying reagents such as angiopoietin-1, prostacyclin, or vascular endothelial growth factor (VEGF) to alter TNF-α-induced endothelial hyperpermeability. Endothelial permeability was measured using the dextran assay or transendothelial electrical resistance. Additionally, a prospective cross-sectional observational study was conducted to analyze circulating EDEV levels in patients with sepsis. EDEVs were examined in HUVEC culture supernatants or patient plasma (nonsepsis, n = 30; sepsis, n = 30; septic shock, n = 42) using flow cytometry. The Wilcoxon rank-sum test was used for comparisons between 2 groups. Comparisons among 3 or more groups were performed using the Steel-Dwass test. Spearman's test was used for correlation analysis. Statistical significance was set at P < .05. RESULTS: TNF-α stimulation of HUVECs significantly increased EDEV release and endothelial permeability. Pretreatment with angiopoietin-1 or prostacyclin suppressed the TNF-α-induced increase in endothelial permeability and inhibited the release of PECAM+ and VE-cadherin+ EDEVs. In contrast, pretreatment with VEGF increased TNF-α-induced endothelial permeability and the release of PECAM+ and VE-cadherin+ EDEVs. However, pretreatment with permeability-modifying reagents did not affect the release of EDEVs expressing inflammatory stimulus-inducible endothelial adhesion molecules such as E-selectin, intracellular adhesion molecule-1, or vascular cell adhesion molecule-1. The number of PECAM+ EDEVs on admission in the septic-shock group (232 [124, 590]/µL) was significantly higher (P = .043) than that in the sepsis group (138 [77,267]/µL), with an average treatment effect of 98/µL (95% confidence interval [CI], 2-270/µL), and the number of VE-cadherin+ EDEVs in the septic-shock group (173 [76,339]/µL) was also significantly higher (P = .004) than that in the sepsis group (81 [42,159]/µL), with an average treatment effect (ATE) of 79/µL (95% CI, 19-171/µL); these EDEV levels remained elevated until day 5. CONCLUSIONS: EDEVs expressing intercellular adhesion molecules (PECAM+ or VE-cadherin+ EDEVs) may reflect increased endothelial permeability and could be valuable diagnostic and prognostic markers for sepsis.


Assuntos
Antígenos CD , Caderinas , Permeabilidade Capilar , Vesículas Extracelulares , Células Endoteliais da Veia Umbilical Humana , Sepse , Índice de Gravidade de Doença , Humanos , Vesículas Extracelulares/metabolismo , Sepse/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Masculino , Estudos Prospectivos , Antígenos CD/metabolismo , Feminino , Pessoa de Meia-Idade , Caderinas/metabolismo , Idoso , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Estudos Transversais , Células Cultivadas , Angiopoietina-1/metabolismo , Biomarcadores/metabolismo , Biomarcadores/sangue , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Endotélio Vascular/metabolismo , Epoprostenol/metabolismo
5.
J Am Heart Assoc ; 13(13): e035990, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38934871

RESUMO

BACKGROUND: Experimental preeclampsia (ePE) has been shown to have worsened outcome from stroke. We investigated the effect of low-dose aspirin, known to prevent preeclampsia, on stroke hemodynamics and outcome, and the association between the vasoconstrictor and vasodilator cyclooxygenase products thromboxane A2 and prostacyclin. METHODS AND RESULTS: Middle cerebral artery occlusion was performed for 3 hours with 1 hour of reperfusion in normal pregnant rats on day 20 of gestation and compared with ePE treated with vehicle or low-dose aspirin (1.5 mg/kg per day). Multisite laser Doppler was used to measure changes in cerebral blood flow to the core middle cerebral artery and collateral vascular territories. After 30 minutes occlusion, phenylephrine was infused to increase blood pressure and assess cerebral blood flow autoregulation. Infarct and edema were measured using 2,3,5-triphenyltetrazolium chloride staining. Plasma levels of thromboxane A2, prostacyclin, and inflammatory markers in plasma and cyclooxygenase levels in cerebral arteries were measured. ePE had increased infarction compared with normal pregnant rats (P<0.05) that was reduced by aspirin (P<0.001). ePE also had intact cerebral blood flow autoregulation and reduced collateral perfusion during induced hypertension that was also prevented by aspirin. Aspirin increased prostacyclin in ePE (P<0.05) without reducing thromboxane B2, metabolite of thromboxane A2, or 8-isoprostane-prostaglandin-2α, a marker of lipid peroxidation. There were no differences in cyclooxygenase levels in cerebral arteries between groups. CONCLUSIONS: Low-dose aspirin in ePE reduced infarction that was associated with increased vasodilator prostacyclin and improved collateral perfusion during induced hypertension. The beneficial effect of aspirin on the brain and cerebral circulation is likely multifactorial and worth further study.


Assuntos
Aspirina , Circulação Cerebrovascular , Circulação Colateral , Modelos Animais de Doenças , Homeostase , Pré-Eclâmpsia , Ratos Sprague-Dawley , Animais , Feminino , Gravidez , Aspirina/administração & dosagem , Aspirina/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Homeostase/efeitos dos fármacos , Circulação Colateral/efeitos dos fármacos , Tromboxano A2/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Ratos , Epoprostenol/metabolismo , Fluxometria por Laser-Doppler
6.
Inflamm Res ; 73(8): 1349-1358, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38832966

RESUMO

OBJECTIVES: Sepsis is a systemic inflammatory disorder characterized by life-threateningorgan dysfunction resulting from a dysregulated host response to infection. Prostacyclin (PGI2) is a bioactive lipid produced by PGI synthase (PGIS) and is known to play important roles in inflammatory reactions as well as cardiovascular regulation. However, little is known about the roles of PGIS and PGI2 in systemic inflammatory responses such as septic shock. METHODOLOGY: Systemic inflammation was induced by intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS) in wild type (WT) or PGIS knockout (KO) mice. Selexipag, a selective PGI2 receptor (IP) agonist, was administered 2 h before LPS injection and again given every 12 h for 3 days. RESULTS: Intraperitoneal injection of LPS induced diarrhea, shivering and hypothermia. These symptoms were more severe in PGIS KO mice than in WT micqe. The expression of Tnf and Il6 genes was notably increased in PGIS KO mice. In contrast, over 95% of WT mice survived 72 h after the administration of LPS, whereas all of the PGIS KO mice had succumbed by that time. The mortality rate of LPS-administrated PGIS KO mice was improved by selexipag administration. CONCLUSION: Our study suggests that PGIS-derived PGI2 negatively regulates LPS-induced symptoms via the IP receptor. PGIS-derived PGI2-IP signaling axis may be a new drug target for systemic inflammation in septic shock.


Assuntos
Sistema Enzimático do Citocromo P-450 , Oxirredutases Intramoleculares , Lipopolissacarídeos , Choque Séptico , Animais , Masculino , Camundongos , Acetamidas/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Citocinas/metabolismo , Epoprostenol , Inflamação/induzido quimicamente , Interleucina-6/genética , Interleucina-6/metabolismo , Oxirredutases Intramoleculares/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pirazinas/farmacologia , Choque Séptico/induzido quimicamente , Choque Séptico/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética
7.
Int J Mol Sci ; 25(12)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38928020

RESUMO

Endometritis is a common disease in animals, leading to disruption of reproductive processes and economic losses. Noradrenergic control of prostaglandin (PG)I2 formation by inflamed endometrium is unknown. We determined the involvement of α1-, α2- and ß-adrenoreceptors (ARs) in noradrenaline-influenced PGI synthase (PGIS) protein abundance and PGI2 release from porcine (1) endometrial explants with Escherichia coli (E. coli)-induced inflammation in vivo, and (2) E. coli lipopolysaccharide (LPS)-treated endometrial epithelial cells. Experiment 1. E. coli suspension (E. coli group) or saline (CON group) was injected into the uterine horns. In both groups, noradrenaline increased endometrial PGIS abundance and PGI2 release versus the control values, and it was higher in the E. coli group than in the CON group. In the CON group, a noradrenaline stimulating effect on both parameters takes place through α1D-, α2C- and ß2-ARs. In the E. coli group, noradrenaline increased PGIS abundance and PGI2 release via α1A-, α2(B,C)- and ß(1,2)-ARs, and PGI2 release also by α2A-ARs. Experiment 2. LPS and noradrenaline augmented the examined parameters in endometrial epithelial cells versus the control value. In LPS-treated cells, ß(1,2)-ARs mediate in noradrenaline excitatory action on PGIS protein abundance and PGI2 release. ß3-ARs also contribute to PGI2 release. Under inflammatory conditions, noradrenaline via ARs increases PGI2 synthesis and release from the porcine endometrium, including epithelial cells. Our findings suggest that noradrenaline may indirectly affect processes regulated by PGI2 in the inflamed uterus.


Assuntos
Endométrio , Epoprostenol , Norepinefrina , Animais , Feminino , Norepinefrina/metabolismo , Endométrio/metabolismo , Endométrio/patologia , Suínos , Epoprostenol/metabolismo , Receptores Adrenérgicos/metabolismo , Lipopolissacarídeos , Inflamação/metabolismo , Inflamação/patologia , Escherichia coli , Endometrite/metabolismo , Endometrite/patologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Oxirredutases Intramoleculares/metabolismo , Sistema Enzimático do Citocromo P-450
8.
Clin Chim Acta ; 561: 119837, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38945284

RESUMO

Treprostinil (Remodulin®) is a Food and Drug Administration (FDA) approved prostacyclin analog to treat pulmonary arterial hypertension. Recently, treprostinil has been investigated to reduce ischemia-reperfusion injury (IRI) during transplantation, which currently has no approved treatment. A validated analytical method is necessary to measure treprostinil concentrations in biological specimens. Here, a novel, sensitive, and specific method to measure treprostinil concentrations in rat serum, human serum, and human plasma has been developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Biological samples were processed by protein precipitation before chromatography and 6-keto Prostaglandin F1α-d4 was used as an internal standard. A gradient method was established with a total run time of 4 min. The assay was linear over the range of 0.25-75.0 ng/ml with accuracy (92.97-107.87 %), intra-assay precision (1.16-3.34 %), and inter-assay precision (1.11-4.58 %) in all biological matrices, which are within FDA acceptance criteria. No significant variation in treprostinil or 6-keto Prostaglandin F1α-d4 concentrations were observed under the investigated storage conditions. This novel, sensitive, and specific LC/MS-MS method is cost-effective and suitable for measuring treprostinil concentrations in animal studies and human biological samples for clinical applications.


Assuntos
Epoprostenol , Traumatismo por Reperfusão , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Humanos , Animais , Epoprostenol/análogos & derivados , Epoprostenol/sangue , Ratos , Cromatografia Líquida/métodos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/sangue , Masculino , Ratos Sprague-Dawley
9.
Cell Mol Life Sci ; 81(1): 264, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38878214

RESUMO

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.


Assuntos
Angiotensina II , Fibrilação Atrial , Remodelamento Atrial , Epoprostenol , Camundongos Endogâmicos C57BL , Transdução de Sinais , Animais , Fibrilação Atrial/metabolismo , Fibrilação Atrial/patologia , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/prevenção & controle , Camundongos , Humanos , Masculino , Transdução de Sinais/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Epoprostenol/metabolismo , Fibrose , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/efeitos dos fármacos , Iloprosta/farmacologia , Receptores de Epoprostenol/metabolismo , Receptores de Epoprostenol/genética , Feminino
10.
Expert Opin Pharmacother ; 25(6): 717-725, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38832823

RESUMO

INTRODUCTION: Following the INPULSIS and ASCEND studies, leading to the first two approved antifibrotic therapies for patients with IPF, ongoing investigations are firmly exploring novel agents for a targeted effective and better tolerated therapy able to improve the natural history of the disease. AREAS COVERED: This review aims to analyze recent advances in pharmacological research of IPF, discussing the currently available treatments and the novel drugs under investigation in phase 3 trials, with particular emphasis on BI 1015550 and inhaled treprostinil. The literature search utilized Medline and Clinicaltrials.org databases. Critical aspects of clinical trial design in IPF are discussed in light of recently completed phase III studies. EXPERT OPINION: While randomized clinical trials in IPF are currently underway, future objectives should explore potential synergistic benefits when combining novel molecules with the existing therapies and identify more specific molecular targets. Moreover, refining the study design represent another crucial goal. The aim of the pharmacological research will be not only stabilizing but also potentially reversing the fibrotic changes in IPF.


Assuntos
Fibrose Pulmonar Idiopática , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Antifibróticos/uso terapêutico , Antifibróticos/farmacologia , Animais , Terapia de Alvo Molecular , Projetos de Pesquisa , Administração por Inalação , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico
11.
Eur Respir J ; 63(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38811045

RESUMO

BACKGROUND: Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study (ClinicalTrials.gov: NCT03496623) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. METHODS: Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12. RESULTS: In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. CONCLUSIONS: The risk-benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.


Assuntos
Anti-Hipertensivos , Estudos Cross-Over , Epoprostenol , Hipertensão Pulmonar , Doença Pulmonar Obstrutiva Crônica , Teste de Caminhada , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/complicações , Epoprostenol/análogos & derivados , Epoprostenol/administração & dosagem , Epoprostenol/uso terapêutico , Feminino , Masculino , Hipertensão Pulmonar/tratamento farmacológico , Administração por Inalação , Idoso , Pessoa de Meia-Idade , Método Duplo-Cego , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Resultado do Tratamento
13.
J Vet Intern Med ; 38(4): 2333-2338, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38662965

RESUMO

An 8-year-old Leonberger receiving immunosuppressive treatment with clinical signs of acute dyspnea, cyanosis, and difficulty standing was referred to our institution (Day 1). Treatment including oxygen, clopidogrel, and low-molecular-weight heparin was initiated for suspected pulmonary thrombosis. However, exertional dyspnea persisted until Day 10, and increased tricuspid regurgitation velocity, pulmonary vascular resistance, and McConnell's signs also were observed. Thus, beraprost sodium was administered PO on Day 11 to treat suspected pulmonary hypertension. On Day 13, contrast-enhanced computed tomography identified extensive contrast defects in the pulmonary arteries, and IV monteplase was administered on Days 14 and 18, with marked improvement in respiratory status and exertional dyspnea on Day 20. Right ventricular function and McConnell signs also improved, and tricuspid regurgitation velocity and pulmonary vascular resistance decreased. On Day 250, echocardiography indicated further improvement in pulmonary hypertension pathophysiology. The patient was still progressing well with antithrombotic and pulmonary vasodilator treatment 400 days later.


Assuntos
Fibrinolíticos , Hipertensão Pulmonar , Vasodilatadores , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/veterinária , Animais , Fibrinolíticos/uso terapêutico , Vasodilatadores/uso terapêutico , Cães , Doenças do Cão/tratamento farmacológico , Masculino , Epoprostenol/uso terapêutico , Epoprostenol/análogos & derivados , Trombose/tratamento farmacológico , Trombose/veterinária
14.
BMJ Open Respir Res ; 11(1)2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38479818

RESUMO

OBJECTIVES: Vasoactive drugs have exhibited clinical efficacy in addressing pulmonary arterial hypertension, manifesting a significant reduction in morbidity and mortality. Pulmonary hypertension may complicate advanced interstitial lung disease (PH-ILD) and is associated with high rates of disability, hospitalisation due to cardiac and respiratory illnesses, and mortality. Prior management hinged on treating the underlying lung disease and comorbidities. However, the INCREASE trial of inhaled treprostinil in PH-ILD has demonstrated that PH-ILD can be effectively treated with vasoactive drugs. METHODS: This comprehensive systematic review examines the evidence for vasoactive drugs in the management of PH-ILD. RESULTS: A total of 1442 pubblications were screened, 11 RCTs were considered for quantitative synthesis. Unfortunately, the salient studies are limited by population heterogeneity, short-term follow-up and the selection of outcomes with uncertain clinical significance. CONCLUSIONS: This systematic review underscores the necessity of establishing a precision medicine-oriented strategy, directed at uncovering and addressing the intricate cellular and molecular mechanisms that underlie the pathophysiology of PH-ILD. PROSPERO REGISTRATION NUMBER: CRD42023457482.


Assuntos
Hipertensão Pulmonar , Doenças Pulmonares Intersticiais , Humanos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/complicações , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Anti-Hipertensivos/uso terapêutico , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Epoprostenol/administração & dosagem , Vasodilatadores/uso terapêutico , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Tex Heart Inst J ; 51(1)2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38483473

RESUMO

Portopulmonary hypertension is a rare condition with a poor prognosis. Prompt management is essential for liver transplantation eligibility, a potentially curative option. This report presents a case of severe portopulmonary hypertension that resolved with a conservative therapeutic regimen of tadalafil, macitentan, and inhaled treprostinil, which ultimately enabled successful liver transplantation. There was no recurrence of pulmonary hypertension after transplantation, and the patient was weaned off most pulmonary arterial hypertension therapies. This case report is the first to provide evidence that inhaled treprostinil is a safe and effective alternative to continuous intravenous prostacyclins in portopulmonary hypertension.


Assuntos
Epoprostenol , Hipertensão Pulmonar , Transplante de Fígado , Humanos , Epoprostenol/análogos & derivados , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Doenças Raras
17.
Eur J Cardiothorac Surg ; 65(4)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38539035

RESUMO

OBJECTIVES: Preoperative intravenous epoprostenol therapy can cause thrombocytopaenia, which may increase the risk of perioperative bleeding during lung transplantation. This study aimed to determine whether lung transplantation can be safely performed in patients with epoprostenol-induced thrombocytopaenia. METHODS: From June 2008 to July 2022, we performed 37 lung transplants in patients with pulmonary arterial hypertension (PAH), including idiopathic PAH (n = 26), congenital heart disease-associated PAH (n = 7), pulmonary veno-occlusive disease (n = 3) and peripheral pulmonary artery stenosis (n = 1) at our institution. Of these, 26 patients received intravenous epoprostenol therapy (EPO group), whereas 11 patients were treated with no epoprostenol (no-EPO group). We retrospectively analysed the preoperative and postoperative platelet counts and post-transplant outcomes in each group. RESULTS: Preoperative platelet counts were relatively lower in the EPO group than in the no-EPO group (median EPO: 127 000 vs no-EPO: 176 000/µl). However, blood loss during surgery was similar between the 2 groups (EPO: 2473 ml vs no-EPO: 2615 ml). The platelet counts significantly increased over 1 month after surgery, and both groups showed similar platelet counts (EPO: 298 000 vs no-EPO: 284 000/µl). In-hospital mortality (EPO: 3.9% vs no-EPO: 18.2%) and the 3-year survival rate (EPO: 91.4% vs no-EPO: 80.8%) were similar between the 2 groups. CONCLUSIONS: Patients with PAH treated with intravenous epoprostenol showed relatively lower platelet counts, which improved after lung transplantation with good post-transplant outcomes.


Assuntos
Hipertensão Pulmonar , Transplante de Pulmão , Hipertensão Arterial Pulmonar , Trombocitopenia , Humanos , Epoprostenol/uso terapêutico , Epoprostenol/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/cirurgia , Estudos Retrospectivos , Hipertensão Pulmonar Primária Familiar , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico
19.
BMJ Open Respir Res ; 11(1)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38519114

RESUMO

BACKGROUND: Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. METHODS: Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and <5 WU versus ≥5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. RESULTS: Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs -10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. CONCLUSION: Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.


Assuntos
Epoprostenol , Hipertensão Pulmonar , Doenças Pulmonares Intersticiais , Humanos , Teorema de Bayes , Epoprostenol/análogos & derivados , Hemodinâmica , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Eur Heart J ; 45(21): 1937-1952, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38416633

RESUMO

BACKGROUND AND AIMS: Effective therapies that target three main signalling pathways are approved to treat pulmonary arterial hypertension (PAH). However, there are few large patient-level studies that compare the effectiveness of these pathways. The aim of this analysis was to compare the effectiveness of the treatment pathways in PAH and to assess treatment heterogeneity. METHODS: A network meta-analysis was performed using individual participant data of 6811 PAH patients from 20 Phase III randomized clinical trials of therapy for PAH that were submitted to the US Food and Drug Administration. Individual drugs were grouped by the following treatment pathways: endothelin, nitric oxide, and prostacyclin pathways. RESULTS: The mean (±standard deviation) age of the sample was 49.2 (±15.4) years; 78.4% were female, 59.7% had idiopathic PAH, and 36.5% were on background PAH therapy. After covariate adjustment, targeting the endothelin + nitric oxide pathway {ß: 43.7 m [95% confidence interval (CI): 32.9, 54.4]}, nitric oxide pathway [ß: 29.4 m (95% CI: 22.6, 36.3)], endothelin pathway [ß: 25.3 m (95% CI: 19.8, 30.8)], and prostacyclin pathway [oral/inhaled ß: 19.1 m (95% CI: 14.2, 24.0), intravenous/subcutaneous ß: 24.4 m (95% CI: 15.1, 33.7)] significantly increased 6 min walk distance at 12 or 16 weeks compared with placebo. Treatments also significantly reduced the likelihood of having clinical worsening events. There was significant heterogeneity of treatment effects by age, body mass index, hypertension, diabetes, and coronary artery disease. CONCLUSIONS: Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH, with significant treatment heterogeneity in patients with some comorbidities. Randomized clinical trials are warranted to identify the most effective treatment strategies in a personalized approach.


Assuntos
Anti-Hipertensivos , Humanos , Anti-Hipertensivos/uso terapêutico , Feminino , Pessoa de Meia-Idade , Epoprostenol/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Óxido Nítrico/metabolismo , Masculino , Hipertensão Arterial Pulmonar/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Endotelinas/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Resultado do Tratamento
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